Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic System
  • C07F13/005—Compounds without a metal-carbon linkage
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
  • C07D215/24—Oxygen atoms attached in position 8
  • C07D215/26—Alcohols; Ethers thereof

Definitions

• the present invention relates to diagnosis and therapy within the field of biomedical optics. More particularly, the invention relates to novel ligands for forming metal complexes that absorb or fluoresce in the visible or near-infrared (NIR) region of the electromagnetic spectrum, new complexes incorporating such ligands, process for preparing such complexes, and methods of imaging or therapy using such agents.
• NIR near-infrared
• Metal ions continue to play a major role in diagnostic and therapeutic medicine.
• radionuclide metal complexes derived from both transition and lanthanide elements are being used extensively in diagnostic and therapeutic nuclear medicine procedures
• paramagnetic complexes are being used extensively in magnetic resonance imaging procedures
• platinum complexes have long been used as cancer chemotherapeutic agents.
• metal complexes that absorb or emit in the visible or near-infrared (NIR) region have made a significant impact in the field of biomedical optics and have a great potential for photodiagnostic and phototherapeutic applications (J. N. Demas and B. A. DeGraff. Design and Applications of Highly Luminescent Transition Metal Complexes, Analytical Chemistry, 1991, 63, 829-837; M. P.
• Suitable metal ions for optical applications include Cr(III), Os(II), Ru(II), Ni(II), Eu(III), Tb(III), Lu(III), Yb(III), Er(III), and Nd(III). Eu(III), and Tb(III) are particularly preferred because of favorable absorption and emission properties in visible and NIR regions.
• metal ion transition and lanthanide
• metal ion transition and lanthanide
• Energy transfer from aromatic donors (referred to as “antennae”) to the lanthanide metal ion directly bounded to the donor group results in large increase in lanthanide fluorescence (S. I. Weissman, Journal of Chemical Physics, 1942, 10, 214; B. Alpha et al.
• thermodynamic stability constant indicates the affinity of totally unprotonated ligand for a metal ion.
• conditional stability constant indicates the stability of the complex under physiological pH. Ion selectivity of the ligand toward the desired metal ion over other endogenous metal ions such as zinc, iron, magnesium, and calcium, determines the rate of release of the metal ion into the vascular or extracellular space. The released metal ion is capable of crossing the blood-brain barrier and thereby perturbing the neurophysiology.
• Thermodynamically and kinetically stable metal complexes can be achieved with a proper choice of ligands systems. Transition metal ions generally require soft donors such as thiols and phosphines, whereas lanthanide ions require hard donors such as carboxylates or amines.
• unsaturated heterocyclic bases such as pyridines, imidazoles, and the like are excellent coordinators to both types of metal ions. Numerous pyridine, quinoline, and imidazole based metal complexes have been prepared and many of them have been conjugated to bioactive carriers such as immunoglobulins (R. Rajagopalan et al.
• the present invention specifically pertains to novel quinoline based heterocyclic N 2 O 3 , N 3 O 3 , N 3 O 4 , and N 2 OS ligands that are suitable for complexing metal ions, and are useful as general imaging, diagnostic, or therapeutic agents employing optical, nuclear medicine, or magnetic resonance procedures.
• the principal advantages of this invention are: (a) the metal ion is directly bounded to the “antenna” portion of the molecule, and (b) the entire complex is rigid. Both of these factors are expected to contribute to significant enhancement of absorption and luminescence properties compared to those metal complexes where the antenna is either located remote from the metal ion or has considerable degrees of freedom.
• the present invention provides new and structurally diverse compositions comprising complexing agents (ligands) of the general Formula 1,
• R 1 to R 5 may the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, —OH, C1-C10 polyhydroxyalkyl, C1-C10 alkoxyl, C1-C10 alkoxyalkyl, —SO 3 H, —(CH 2 ) m —CO 2 H and —NR 6 R 7 ;
• R 6 and R 7 may the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 aryl, and C1-C10 polyhydroxyalkyl;
• m ranges from 0 to 10;
• a 1 is selected from the group consisting of —OH, —CO 2 H, —N(R 8 )(R 9 ), —SPg —CONHR 10 and —HNCOR 11 ;
• R 8 and R 9 may the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 aryl
• ligands according to the present invention have the general formula of Formula 1 above wherein R 1 to R 5 are selected from the group consisting of hydrogen, —OH, C1-C10 alkoxyl, —(CH 2 ) m —CO 2 H, and —N(R 6 )(R 7 ); A 1 is selected from the group consisting of —OH, —N(R 8 )(R 9 ), and —HNCOR 11 ; B 1 is —CHR 13 ; C 1 is selected from the group consisting of hydrogen, C1-C10 alkyl, —(CH 2 ) m CO 2 H, —CH 2 CH 2 —N(CH 2 CO 2 H) 2 , and —COCH(R 16 )—SPg; D 1 is selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 polyhydroxyalkyl, —(CH 2 ) m —CO 2 H, and —CH 2 CH 2 —N(CH
• ligands according to the present invention have the general formula of Formula 1 above wherein R 1 to R 5 are hydrogens; A 1 is —OH or —N(CH 2 CO 2 H) 2 ; B 1 is —CH 2 —; C 1 is selected from the group consisting of —CH 2 —CO 2 H, —CH 2 CH 2 —N(CH 2 CO 2 H) 2 , and —COCH 2 —SPg; D 1 is selected from the group consisting of hydrogen, C1-C10 alkyl, and —CH 2 —CO 2 H; and Pg is selected from the group consisting of benzoyl, tetrahydropyranyl, and methoxycarbonyl.
• the present invention also provides structurally diverse compositions comprising metal complexes of the general formula of Formula 2 formed by coordination of an appropriate metal ion to the ligands derived from Formula 1 shown above,
• R 17 to R 21 may the same or different and are defined in the same manner as R 1 ;
• a 2 is selected from the group consisting of —O ⁇ , —CO 2 ⁇ , —N(R 8 )(R 9 ), —SPg —CON(R 10 ), and —NCOR 11 ;
• R 8 and R 9 may the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 aryl, C1-C10 polyhydroxyalkyl, —(CH 2 ) m CO 2 ⁇ , and —(CH) 2 —N(CH 2 CO 2 ⁇ ) 2 ;
• R 10 is selected from the group consisting of hydrogen, C1-C10, alkyl, C1-C10 aryl, C1-C10 polyhydroxyalkyl, and —(CH 2 ) 2 —S;
• R 11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C1-
• the complexes according to the present invention have the general formula of Formula 2 above wherein R 17 to R 21 are selected from the group consisting of hydrogen, —O ⁇ , C1-C10 alkoxyl, —(CH2) m —CO 2 ⁇ ; and —N(R 6 )(R 7 ); A 2 is selected from the group consisting of —O ⁇ ; —N(R 8 )(R 9 ), and —HNCOR 11 ; B 2 is —CHR 13 ; C 2 is selected from the group consisting of hydrogen, C1-C10 alkyl, —(CH 2 )mCO 2 ⁇ , —CH 2 CH 2 —N(CH 2 CO 2 ⁇ ) 2 , and —COCH(R 16 )—S ⁇ ; D 2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 polyhydroxyalkyl, —(CH 2 )mCO 2 ⁇ , and
• the complexes according to the present invention have the general formula of Formula 2 above wherein R 17 to R 21 are hydrogens; A 2 is —O ⁇ or —N(CH 2 CO 2 ⁇ ) 2 ; B 2 is —CH 2 —; C 2 is selected from the group consisting of —CH 2 —CO 2 ⁇ , —CH 2 CH 2 —N(CH 2 CO 2 ⁇ ) 2 , and —COCH 2 —S ⁇ ; D 2 is selected from the group consisting of hydrogen, C1-C10 alkyl, and —CH 2 —CO 2 ⁇ ; and M is a metal ion having an atomic number of 24-26, 28, 31, 43, 44, 49, 62-65, 71, 75, or 76.
• compositions of the invention are suitable for use with a variety of other modalities including X-rays, magnetic resonance, and radiographic imaging. Electron donating and electron releasing groups at various positions in the ligands of Formula 1 and the metal complexes Formula 2 provide an opportunity to alter the absorption and emission properties of the molecule thereby enhancing the optical utility of these molecules. Also, these additional functionalities afford the capability of conjugation to biomolecules and synthetic polymers for selective delivery to various organs or tissues of interest.
• biomolecule refers to all natural and synthetic molecules that play a role in biological systems.
• Biomolecules include hormones, amino acids, peptides, peptidomimetics, proteins, nucleosides, nucleotides, nucleic acids, carbohydrates, lipids, albumins, mono- and polyclonal antibodies, receptor molecules, receptor binding molecules, synthetic polymers, and aptamers.
• Specific examples of biomolecules include inulins, prostaglandins, growth factors, growth factor inhibitors like somatostatin, liposomes, and nucleic acid probes.
• Example of synthetic polymers include polylysine, polyaspartic acid, polyarginine, aborols, dendrimers, and cyclodextrins. The advantages of biomolecules include enhance tissue targeting through specificity and delivery.
• the complexes of the present invention may vary widely depending on the contemplated application.
• fluorescent compounds absorbing and emitting in the near infrared (NIR) region i.e. 650-900 nm
• dyes absorbing and emitting in the region of 350-950 nm, preferably 600-900 nm are desirable.
• the carrier molecules may also vary widely.
• albumin or methylated serum albumin is preferable.
• polysaccharides or anionic polypeptides are desirable.
• antibodies, peptides, or carbohydrates directed against specific cell surface markers are preferred.
• Diagnostic compositions comprising the compounds of the invention are also provided. Methods of performing diagnostic procedures with compositions of the invention are also disclosed. The method comprises administering an effective amount of a composition of the invention contained in a pharmaceutically acceptable formulation to a patient either systemically or locally to the organ or tissue to be studied. It is believed that the novel compositions of the present invention have broad clinical utility, which includes, but is not limited to, diagnostic imaging of tumors, of inflammation (both sterile and bacterial), and of impaired vasculature; laser guided endoscopic examination of sites of lesion; and photodynamic and chemotherapy of tumors or infection.
• compositions of this invention can be formulated into diagnostic or therapeutic compositions for enteral, parenteral, or oral administration.
• These compositions contain an effective amount of the metal complexes along with conventional pharmaceutical carriers and excipients appropriate for the type of administration contemplated.
• These compositions may also include stabilizing agents selected from the class consisting of mono- or polycarboxylic acids, mono- or polyamines, mono- or polynucleotides, mono or polysaccharides, amino acids, and peptides.
• parenteral administration advantageously contains a sterile aqueous solution or suspension of the complexes whose concentration ranges from about 1 nM to about 0.5 M.
• Preferred parenteral formulations have a concentration of 1 ⁇ M to 10 mM.
• Such solutions also may contain pharmaceutically acceptable buffers, emulsifiers, surfactants, and, optionally, electrolytes such as sodium chloride.
• Concentrations of the metal complexes of this invention in formulations for enteral administration may vary widely as is well-known in the art. In general, such formulations are liquids which include an effective amount of the complexes in aqueous solution or suspension.
• Such enteral composition may optionally include buffers, surfactants, emulsifiers, thixotropic agents, and the like.
• Compositions for oral administration may also contain flavoring agents and other ingredients for enhancing their organoleptic qualities.
• the diagnostic compositions are administered in doses effective to achieve the desired diagnostic or therapeutic objective. Such doses may vary widely depending upon the particular complex employed, the organs or tissues to be examined, the equipment employed in the clinical procedure, and the like.
• the diester obtained above was treated with 96% formic acid (20 mL) and kept at ambient temperature for 24 hours. Excess formic acid was removed by evaporation in vacuo and the brown residue was treated with water (25 mL), and filtered hot (gravity filtration). Upon cooling, the product crystallized as a red solid which was filtered and dried to furnish 1.1 g of the ligand of Formula 3.
• a solution of the ligand of Formula 3 (145 mg, 0.5 mmol) and iron acetylacetonate (177 mg, 0.5 mmol) in dimethylformamide (2 mL) is treated with two drops of water and the entire mixture is heated at 100-120° C. for 16 hours. After cooling the reaction mixture to ambient temperature, the solution is poured onto ethyl ether. The precipitate is collected by filtration and is purified by either recrystallization or C-18 reverse phase chromatography to give the iron complex of Formula 5.
• the triester obtained above (820 mg) was treated with 96% formic acid (10 mL) and heated at 80-90° C. for 15 minutes and thereafter kept at ambient temperature for 24 hours. Excess formic acid was removed by evaporation in vacuo and the residue was triturated with acetone (50 mL). The solid was collected by filtration and dried to give 520 mg of the ligand of Formula 7 as a pale pink solid.
• a mixture of the ligand of Formula 7 (798 mg, 2 mmol) and lutetium oxide (398 mg, 1 mmol) in deionized, distilled water (10 mL) is heated under reflux for 24 hours.
• the solution is filtered through fine porosity sintered glass funnel to remove undissolved impurities and the filtrate is poured onto acetone (200 mL).
• the precipitate is collected, washed with acetone, and dried.
• the crude lutetium complex of Formula 9 is purified by C-18 reverse phase chromatography.
• a mixture of the ligand of Formula 7 (780 mg, 2 mmol) and gadolinium oxide (362 mg, 1 mmol) in deionized, distilled water (10 mL) is heated under reflux for 24 hours.
• the solution is filtered through fine porosity sintered glass funnel to remove undissolved impurities and the filtrate is poured onto acetone (200 mL).
• the precipitate is collected, washed with acetone, and dried.
• the crude gadolinium complex of Formula 11 is purified by C-18 reverse phase chromatography.
• the tetraester obtained above was treated with 96% formic acid (10 mL) and kept at ambient temperature for 24 hours.
• the reaction mixture was poured onto acetone (200 mL) and solid was collected by filtration and dried to furnish the ligand of Formula 12 as an off-white solid.
• a mixture of the ligand of Formula 12 (984 mg, 2 mmol) and lutetium oxide (398 mg, 1 mmol) in deionized, distilled water (10 mL) is heated under reflux for 24 hours.
• the solution is filtered through fine porosity sintered glass funnel to remove undissolved impurities and the filtrate is poured onto acetone (200 mL).
• the precipitate is collected, washed with acetone, and dried.
• the crude lutetium complex of Formula 14 is purified by C-18 reverse phase chromatography.
• a mixture of the ligand of Formula 12 (390 mg, 1 mmol) and chromium acetylacetonate (350 mg, 1 mmol) in dimethylformamide (3 mL) is treated with two drops of water and the entire mixture was heated at 100-120° C. for 24 hours. After cooling the reaction mixture to ambient temperature, the solution is poured onto ethyl ether. The precipitate is collected by filtration, washed with ether, and dried. The crude chromium complex of Formula 15 is purified by crystallization or C-18 reverse phase chromatography.
• a mixture of the ligand of Formula 12 (780 mg, 2 mmol) and gadolinium oxide (362 mg, 1 mmol) in deionized, distilled water (10 mL) is heated under reflux for 24 hours.
• the solution is filtered through a fine porosity sintered glass funnel to remove undissolved impurities and the filtrate is poured onto acetone (200 mL).
• the precipitate is collected, washed with acetone, and dried.
• the crude gadolinium complex of Formula 16 is purified by C-18 reverse phase chromatography.

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